1. Field of the Invention
The present invention pertains to fredericamycin A derivatives and compositions and uses thereof.
2. Background Art
(.+-.)-Fredericamycin A is an antitumor antibiotic by Streotomyces griseus and represents a new structural class of antibiotics containing a spiro[4,4]nonane ring system. See Merck Index, p. 667 (11th ed., 1989). Isolation of the compound together with two biologically inactive components (fredericamycins B and C) was reported by R. Pandey, et al., J. Antibiot., 34, 1389 (1981). The structure of the compound has been confirmed by x-ray crystallography as reported by R. Misra, J. Am. Chem. Soc., 104, 4478 (1982). Spectroscopic and mass spectral characterization was reported in J. Antibiot., 40, 786 (1987).
The biological activity and unique skeletal framework of fredericamycin A has prompted interest in the compound and its synthesis. See, for example, Boger, et al., J. Org. Chem., 56, 2115 (1991); Kelly, et al., J. Am Chem. Soc., 110, 6471 (1988); Kelly, et al., J. Am. Chem. Soc., 108, 7100 (1986); Parker, et al., Tetrahedron Letters. 26, 2181 (1985); Byrne, et al., Biochemistry, 24, 478 (1985); and Rao, et al., Chem. Commun., 1119 (1984). A study of the mechanism of action of fredericamycin A was reported by Hilton, et al., Biochemistry, 25, 5533 (1986). In vitro studies indicate fredericamycin A has cytotoxicity against p388 and L1210 mouse leukemias comparable to doxorubicin and actinomycin. See, Warnick-Pickle, et al., J. Antibiot., 34, 1402 (1981); Chem. Abstr., 1985, 103, 104798c.
Preparation and biological activity of some water soluble salts of fredericamycin A have been reported. See, U.S. Pat. No. 4,673,678 and Misra, J. Antibiot., 51, 976 (1988). Other compounds have been reported in U.S. Pat. No. 4,584,377.